The study of anti-HIV nucleosides different from the more traditional dideoxyribose backbone characteristic of direct DNA chain terminators involved maintaining the critical 3-OH group present in conventional 2'-deoxynucleoside substrates (required for chain extension), but adding a 4-alkyl group (methyl and ethyl) to interfere with the chain elongation step. Last year, synthesis of the thymidine series bearing 4-methyl and 4-ethyl groups was successfully completed and the results showed that the 4-methyl analogue had excellent properties as a delayed chain terminator when used in vitro against HIV-RT as a 5-triphosphate, but failed to be recognized by cellular kinases. This year we have completed the studies on the corresponding 4-methyl and 4-ethyl analogues in the 2-deoxyadenosine series, which in the case of the 4-methyl provided a compound that is both successfully phosphorylated by cellular kinases and extremely potent against HIV in infected cells. This represents the first successful design of a compound in this class capable of being activated by cellular kinases and able to function as an effective delay (kinetic delay) chain terminator of viral DNA synthesis. A patent was filed and a manuscript is being prepared for submission. A recent study reporting that deoxy-L-threosyl phosphonate nucleosides were effective anti HIV agents inspired us to synthesize the conformationally locked, carbocyclic versions of this class of nucleosides. Two extreme conformers: a North-like compound with both groups pseudoaxially oriented and a South-like analogue where both groups are pseudoequatorially oriented were synthesized with adenine as the nucleobase. These compounds, as well as their corresponding enantiomers, were synthesized (Nucleic Acids Symposium Series No. 52, 2008, 623-624). Both North-like pseudoaxial analogue enantiomers proved inactive against HIV in infected cells. The studies on the pseudoequatorially disposed analogues will be completed shortly. The syntheses of the diphosphate analogues (triphosphate mimics) to probe the binding to HIV reverse transcriptase are in progress.